17alpha-oxa-d-homo-pregnanes and methods for their manufacture



United States Patent 3,467,677 17a-OXA-D-HOMO-PREGNANES AND METHODS FOR THEIR MANUFACTURE John N. Gardner, South Mountain Pass, Garrison, N.Y., assignor to Schering Corporation, Bloomfield, N.J., a

corporation of New Jersey No Drawing. Filed Apr. 21, 1967, Ser. No. 632,521 Int. Cl. C07d 101/00; C07c 169/34 US. Cl. 260-345.2 15 Claims ABSTRACT OF THE DISCLOSURE Described herein are novel 3-oxygenated-l6-methyl- 17a oxa D homo 16-pregnenes and 3-oxygenated-16- methyl l7 hydroxy-l7a-oxa-D-homo-pregnanes and 17- alkyl ethers thereof which have anti-androgenic properties.

Also described are methods for the preparation of the above-mentioned 16-methyl-l7a-oxa D homopregnanes which comprise treating a 16B-methyl-l7a-hydroperoxy- 20-keto-pregnane with a strong acid or under non-acidic esterifying conditions whereby is formed a product mixture containing the above-mentioned l6-dehydro and 17 hydroxy 16 methyl 17a oxa-D-homopregnane derivatives; and when a lower alkanol is added to the reaction mixture there is also formed the corresponding 17-alkoxy derivatives of the 17-hydroxy-16-methyl-17aoxa-D-homopregnanes.

BACKGROUND AND SUMMARY OF THE INVENTION Field of the invention This invention relates to new and useful compositions of matter classifiable in the field of organic chemistry as 17a-oxa-D-homosteroids. More particularly, this invention relates to novel 16-methyl-17a-oxa-D-homo-pregnanes and to methods for preparing same.

The invention sought to be patented in its composition aspect is described as residing in the concept of a novel chemical compound having a 16-methyl-17a-oxa-D-homopregnane-ZO-one nucleus and also having either a double bond at 0-16, or a hydroxy group or lower alkyl ether thereof at C-17, said 17a-oxa-D-homo pregnane being further characterized by having an oxygenated function at C-3 selected from the group consisting of ketonic oxygen, (H, fiOH) and (H, aOH). The tangible embodiments of the instant invention may be unsaturated in the A and/or B rings and may also possess substituents at C-6, C-9, C-11 and 0-16.

The process aspect of this invention is described as residing in the concept of treating a 16B-methyl-17a-hydroperoxy-20-keto-pregnane with a strong acid or under nonacidic esterifying conditions whereby fission of the carbon-carbon bond between C-13 and C-l7 occurs followed by the formation of a carbon-oxygen bond giving rise to a l6-methyl-17a-oxa-D-homo-17-acetyl carbonium ion in situ which under the reaction conditions, i.e. in the presence of a strong acid or under non-acidic esterifying conditions, converts to form a mixture comprising 16-methyl-l7a-oxa-D-homo-16-pregnene-20-one and 16B-methyl- 17a-oxa-D-homo-pregnane-17-01. When alcohol is added to the reaction mixture there is also formed the 17-alkoxy derivatives of this invention.

This invention is based uponthe discovery that the tangible embodiments of the composition aspect of my invention disclosed hereinabove are the products of the aforementioned rearrangement process aspect of my invention and that the products, i.e. 16-methyl-17a-oxa-D- homo pregnane 20 ones are anti-androgenic in their physiological action when administered to warm blooded animals and specifically when administered to rats and dogs.

Description of the invention The novel compounds sought to be patented may be represented as a member selected from the group consisting of 16-methyl-l7a-oxa-D-homo-pregnane-ZO-ones of the following structural formulae:

wherein R is a member selected from the group consisting of hydrogen and methyl; R is a member selected from the group consisting of hydrogen and lower alkyl when 0R is B-oriented, and lower alkyl when 0R is a-oriented; W is a member selected from the group consisting of (oxygen), (H, 040V), (H, 50V), V being a member selected from the group consisting of hydrogen and hydrocarbon carbonyl having up to eight carbon atoms; X is a member selected from the group consisting of hydrogen and halogen having an atomic weight less than 126; Y is a member selected from the group consisting of oxygen, (H, aOH), (H, BOH), hydrogen provided X is hydrogen, and (H, {301) provided X is chlorine; Z is a member selected from the group consisting of hydrogen, methyl, fluorine and chlorine; and the l-dehydro, 4-dehydro, S-dehydro, 1,4-bis-dehydro and the 1,5-bis-dehydro analogs thereof.

As used herein the term lower alkyl denotes hydrocarbon radicals of one to five carbon atoms inclusive of the branched chain isomers. Exemplary of the foregoing are such lower alkyl groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like. The preferred lower alkyl groups are methyl and ethyl. The hydrocarbon carboxylic acid esters contemplated at C3 are derived from alkanoic acids such as acetic, propionic, butyric, valeric and isobutyric acids; from alkenoic acids such as butenoic and allylacetic; from alkynoic acids such as propiolic; from aryl, alkaryl and aralkyl carboxylic acids such as benzoic, toluic, and phenylacetic acids respectively.

The use of a wavy line to designate the bonds at C-17 of the Formula I tangible embodiments indicates that both isomeric forms at C-17 (i.e. 170a and 17B-alkoxy-D-homopregnanes and 17/3-hydroxy-D-homo-iso-pregnanes) are included in the composition aspect of this invention. In this application, when a compound name does not specifically indicate the configuration at C-17, both isomeric forms are implicitly included. Thus, the compound name methyl 17a oxa 50c D homo pregnane- 17-ol-3,20-dione 17-methyl ether'includes both the 17mmethoxypregnane and the 17B-methoxy-l7-iso-pregnane isomers i.e. 16B methyl 17a oxa-Sa-D-homo-pregnane- 17OL-O1-3,20-di01'l 17-methyl ether and l6/3-methyl-17aoxa-j'u-D-homo-isopregnane-l7 8-ol-3,ZO-dione 17-methyl ether.

Similarly, the use of the Wavy line to designate the bonds at C5 and C-6 of the Formulae I and II tangible embodiments indicates that both isomeric forms at C-5 and C-6 are included in the composition aspects of this invention. As an example of the foregoing, l6fl-methyl- 17a-oxa-D-homo-pregnane-3,20-dione includes both the 5a-(allo) and the SB-(normal) isomers. Substituents at C-6 may in like manner be either otor fl-oriented and when the name of the compound does not specify an isomer, both isomeric forms are implicity included. Thus the compound name 16,8-methyl-6-fluoro-17a-oxa-D- homo-pregnane-17-ol-3,20-dione 17-ethyl ether includes both the 5a-(allo) and Sfi-(normal) configurations; the 6ocand 6fl-fiuoro substituents and the 17xand 175- ethoxy isomers and combinations thereof.

Included among the tangible embodiments of this invention are such compounds as the following:

16B-methyl-17a-oxa-D-homo-5a-pregnane-17u-ol- 3,20-dione 17-methyl ether, 16fi-methyl-17a-oxa-D-homo-5a-isopregnane-l7f3-ol- 3,20-dione, 16/S-methyl-17a-oxa-D-homo-Sa-isopregnane-35,17,8-diol- -one l7-methyl ether, 16fi-methyl- 17a-oxa-l7-iso-D-homo-4-pregnene-17,8-01- 3,20-dione, 16-methyl-17a-oxa-D-homo-5a-pregnane-3B,16,17-triol- 20-one, 6,l6-dimethyl-17a-oxa-D homo-5,16-pregnadiene-3fl-ol- 20-one 3-acetate, 6,16fi-dimethyl-17a-oxa-l7-iso-D-homo-5-pregnene- 3/3,17;3-diol-20-one 3-acetate, and l6-methyl-17a-oxa-D-homo-4, l 6-pregnadiene-3,20-dione.

PREFERRED EMBODIMENTS OF COMPOSITION ASPECTS OF INVENTION The preferred embodiments of the composition aspect of my invention are those having a 17-oxygenated function, e.g. 16,8-methyl-17a-oxa-D-homo-pregnane-1711-01- 3,20-dione 17-methyl ether, l6fi-methyl-l7a-oxa-17-iso-D- homo-pregnane-l7fi ol-3,20-dione and its 17-n1ethyl ether and the like. The 17-oxygenated compounds usually possess a higher degree of physiological activity than their 16-dehydro analogs. Additionally, the 17a-alkoxy compounds are capable of being converted to the corresponding 17B-alkoxy isomers thereof.

DESCRIPTION OF THE PROCESS ASPECT OF THE INVENTION By the process aspects of this invention a 165-methyll7a-hydroperoxy pregnane upon treatment with a strong acid or under non-acidic esterifying conditions is transformed first into a 16-methyl-17a-oxa-D-homo-17-acetyl carbonium ion in situ. This ion in turn is converted into a mixture of products comprising predominantly a 16- methyl-l6-dehydro-l7a-oxa-D-homopregnane of Formula II together with a 16 3-methyl-l7fl-hydroxy-l7a-oxa-D- homopregnane of Formula I. When a lower alkanol is added to the reaction mixture there are also formed 17- alkoxy derivatives of Formula I, i.e. both the a and [3 isomers, thus producing 17a-alkoxy-17a-oxa-D-homopregnanes and 17 3-alkoxy-17a-oxa-D-homo-iso-pregnanes of this invention.

The physical embodiments of the process aspects of my invention which are carried out under strongly acidic or under non-acidic esterifying conditions include those carried out under strongly acidic non-esterifying conditions (such as that utilizing perchloric acid in dioxane), those carried out under strongly acidic esterifying conditions (e.g. p-toluenesulfonic acid and isopropenyl acetate in acetic acid) and those carried out under non-acidic esterifying conditions (such as acetic anhydride in pyridine). The preferred process is the one employing the non-acidic esterifying conditions.

The 17a-hydroperoxy starting compounds for my processes are, in general, known. They may be prepared by procedures described in the art, such as by reacting an enol form of a 17-desoxy-20-keto pregnane with molecular oxygen under alkaline conditions.

A typical example of a preferred embodiment of this process is set forth below in general terms. A 16,8-methyl- 17a-hydroperoxy-20-keto pregnane, e.g. 16,8-methyl-17ahydroperoxy-Sa-pregnane-3,ZO-dione is dissolved in a suitable tertiary amine, e.g. pyridine to which a stoichiometric excess of a lower alkanoyl anhydride, chloride, or bromide, e.g. acetic anhydride, is added. The mixture is allowed to react over night (18 hours) at about room temperature and is then treated with an aqueous-alcoholic solution of strong base (potassium hydroxide) for about 1 hour in an inert atmosphere. Isolation of the product is effected by precipitation yielding a mixture of tangible embodiments, e.g. 16-methyl-16-dehydro-l7a-oxa-D-homopregnene, 16/3- methyl-l7fl-hydroxy-17a-oxa-D-homopregnane, and 16,8- methyl-17-methoxy-17a-oxa-D-hornopregnane and purification of the tangible embodiments effected by techniques known in the art such as fractional crystallization, partition chromatography on diatomaceous earth, such as, Chromosorb (Iohns-Mansville) or other suitable support using ligroin saturated with propylene glycol or another effective solvent system as the mobile phase. The mixture of products obtained in this manner are depicted in Formulae I and II hereinabove and in which under the conditions recited above the embodiments depicted by Formula II predominate.

Strongly acidic non-esterifying conditions as used herein denote an essentially anhydrous solution of a mineral acid or of an oxygenated sulfur containing acid, e.g. sulfinic, sulfonic, sulfuric and sulfurous acids. These acids are usually employed in conjunction with non-hydroxylic, water miscible, essentially neutral, organic solvents, such as dioxane and tetrahydrofuran. The choice of solvent is frequently dictated by the solubility of the specific 17ahydroperoxide starting material employed. In general, however, dioxane in combination with perchloric acid is preferred. The hydroperoxide, e.g. 6,16fi-dimethyl-l7ahydroperoxy-5-pregnene-3/3-ol-20-one, is dissolved in a suitable solvent (dioxane), a small amount of 70% perchloric acid added and the reaction mixture left overnight (18 hours) at room temperature. The isolation and separation of the products is effected in substantially the same manner as from the esterification medium. Again the 6,l6-dimethyl-l7a-oxa-D-homo-5,1G-pregnadiene-BB- ol-20-one (Formula II embodiment) predominates, however, the 6,16B-dimethyl-l7a-oxa-D-homo-5-pregnene-3B, 17B-diol-20-one (l7-oxygenated analog) (Formula I) is concomitantly obtained.

Exemplary of the third medium in which the instant invention may be performed, i.e. esterifying conditions which are strongly acidic, are such as that utilizing isopropenyl acetate, for example, in combination with a strong acid (p-toluenesulfonic acid) in an alkanoic (acetic) acid solvent. The choice of strong acid does not appear to be critical, however, the medium should be essentially anhydrous. The process is carried out in essentially the same manner as the two described above and the product contains a preponderance of the Formula II embodiment.

The processes described generally above will be more fully shown in the examples.

As previously stated, the tangible embodiments of this invention are anti-androgens. As defined herein the term anti-androgen is used to designate compounds and pharmaceutical formulations thereof, which cause a reduction or remission of disorders caused or aggravated by androgens. Benign prostatic hypertrophy is such a disorder and is one with which domestic animals, especially dogs, be-

u come afflicted. The tangible embodiments of this invention are effective in treating such an affliction. They may be employed in capsules, tablets and elixirs for oral administration. They may also be employed in the form of injectables and in either case may be compounded with pharmaceutically acceptable excipients. These compounds may also be used in the form of suppositories which may additionally contain local anesthetics.

The following examples are set forth to describe the best mode contemplated for carrying out this invention and are not to be construed as limiting the scope thereof.

EXAMPLE 1A 6,16-dimethyl-l7a-oxa-D-homo-5,16-pregnadiene-3flol--one 3-acetate Dissolve 3.1 g. of 6,16-dimethyl-17a-hydroperoxy-S- pregnen-3B-ol-20-one in a mixture of 20 ml. of pyridine and 5 ml. of acetic anhydride at room temperature and with stirring. Allow the reaction mixture to stir for approximately 18 hours at room temperature. Precipitate the product by slowly pouring the reaction mixture into ice water with vigorous stirring. Collect the product on a filter and wash it with copious quantities of water. Crystallize the product from aqueous methanol and obtain 1.03 g. 6,16-dimethyl 17a oxa-D-homo-5,16-pregnadiene-3/3-0l-20-one 3-acetate having the following properties: M.P. 180183 c. [a] =l69, x 278 mp. (e=6,200).

Treat the following 17a-hydroperoxy steroids in the manner described above:

1 6 B-methyl- 17 a-hydroperoxy-5a-pregnane-3 6-ol-20-one 3-acetate 16B-methyl-1 7a-hydroperoxy-5-pregnene-3 8-01-20-one 3-acetate 16 fl-methyl- 17a-hydroperoxy-4-pre gnene-3,20-dione 16fi-methyl- 17 a-hydroperoxy- 1 ,4-pregnadiene-1 100-01- 3 ,20-dione 6a,16fi-dimethyl-17a-hydroperoxy-4-pregnene-3,20-di0ne 16,6-methyl-17a-hydroperoxy-5a-pregnane-3B-ol-1 1,20-

dione 16fl-methyl-17ot-hydroperoxy-6a-fiuoro-5-pregnene-3 3- ol-20-one 16/3-methyl-17a-hydroperoxy-pregnane-3 ,1 1,20-trione 16fi-methy1-17a-hydroperoxy-5a-pregnane-3 ,1 1,20-trione 16/3-methyl-17 a-hydroperoxy-pregnane-3 a-o1-20-one 3-acetate 16/S-methyl-17a-hydroperoxy-1,4-pregnadiene-1 15-01- 3 ,ZO-dione and 16,6-methyl- 1 7u-hydroperoxy-9 11,1 1/3-dichloro-4-pregnene- 3,20-dione.

The compounds listed above, upon reaction under the conditions of Example 1A yield respectively the following products:

16-methyl-17a-oxa-D-homo-16,5ot-pregnene-3[3-ol-20-one 3-acetate 16-methyl-17a-oxa-D-homo-5,16-pregnadiene-3fi-ol-20- one 3 -acetate 16-rmethyl-17a-oXa-D-hom0-4,16-pregnadiene-3,20-dione 16-methyl-17a-oxa-D-homo-1,4,16-pregnatriene-1 1 u-ol- 3,20-dione ll-acetate 601,1 6-dimethyl- 17a-oxa-D-homo-4, 16-pregnadiene-3,20-

dione 16-methyl-17a-oxa-5a,16-pregnene-3/3-o1-11,20-dione 3-acetate 16-methyl-17a-oxa-D-homo-6a-fluoro-S,16-pregnadiene- 3 fl-ol-20-one S-acetate 16-methyl-17a-oxa-D-homo-16-pregnene-3 ,1 1,20-trione 16-methyl-17a-oxa-D-homo-5a,16-pregnene-3,11,20-

trione 16-methyl-17a-oxa-D-hqmo-16-pregnene-3B-ol-20-one 3-acetate 16-methyl-17a-oxa-D-h0mo-1,4,16-pregnatriene-1lfi-ol- 3,20-dione and 16-methyl-17 a-oxa-D-homo-9a,l1fi-dichloro-4,16-pregnadiene-3,20-dione.

EXAMPLE 1B 6,l6,6-dimethyl-17a-oxa-D-homo-17-iso-5-pregnene-3 5, 17 B-diol-ZO-one 3-acetate Treat the aqueous methanol filtrates from Example 1A containing approximately 2 g. of solids wrth excess potassium hydroxide at room temperature for 2 hours under a nitrogen atmosphere. Neutralize the reaction mixture with acetic acid and dilute the mixture with 5 volumes of Water per volume of reaction mixture. Extract the diluted mixture with ethyl acetate and wash the extracts with water. Dry the extracts over sodium sulfate and concentrate under reduced pressure to a residue. Dissolve the residue in a small volume (25 ml.) of propylene glycol and chromatograph on a previously prepared column containing 140 g. of Chromosorb suspended in propylene glycol saturated with ligroin. Develop the column with ligroin saturated with propylene glycol; collect 50 ml. fractions and monitor the efiluent by paper chromatographing a portion of each using the same system being used in the column. Combine the fractions containing materials of like mobility, fractions 53-72 contain the title product as the 35-0]. Concentrate the combined fractions under reduced pressure to a residue and redissolve in pyridine and add a molar excess of acetic anhydride to the solution obtained. Allow the reaction mixture to stand overnight (18 hours) and precipitate into water. Water wash and dry the product and crystallize from aqueous ethanol to obtain 6,16-dimethyl-17a-oxa-D-homo- 17-iso-5-pregnene-3fi,17fl-diol-20-one 3-acetate; which melts at 149-153 C.

EXAMPLE 2 1G-methyl-l7a-oxa-D-homo-5a,16-pregnene-3B-ol-20-one Dissolve 1.22 g. of 17u-hydroperoxy-IGB-methyl-Sapregnane-3/3-ol-20-one 3-acetate in a mixture of 7 ml. of pyridine and 3.5 ml. of acetic anhydride. Permit the resulting solution to stand at room temperature for 18 hours. Pour the solution into 5 volumes (50 ml.) of water and extract the product with ethyl acetate. Evaporate the extract to a residue under reduced pressure and dissolve the residue in methanol. With stirring and under a nitrogen atmosphere, add a solution of 2 N potassium hydroxide to the methanolic solution until it becomes strongly basic (pH 12). Allow the reaction to proceed for 1 hour under the inert atmosphere, then precipitate by the addition of water.

Filter, water wash, and dry the resultant precipitate comprising 16 methyl-17a-oxa-D-homo-5a,16-pregnene- 3{3ol-20-one.

Purify by chromatography on Chromosorb g.) using the ligroin-propylene glycol system described above. Collect 30 ml. fractions and combine the fractions containing like products as determined by thin layer chromatography of an aliquot of each fraction. Fractions 3264 contain the title product whose physical constants are as follows: M.P. 159-162 C. [a] -79 .5 dioxane, and a polymorphic form M.P. 128-132", said polymorph being convertible into the higher melting form.

By employing the process of Example 2, the following 17a-hydroperoxy pregnanes are converted to their corresponding 17a-oxa-D-homo-16-pregnene analogs:

16;3-n1ethyl-17 a-hydroperoxy-5-pregnene-3 [3-01-2-0-one S-acetate 16/8-methyl-17a-hydroperoxy-4-pregnene-3,20-dione 16,8-methyl-17a-hydroperoxy-1,4-pregnadiene-1 1a-ol-3,

20-dione 6oz,16 3-dimethyl-17a-hydroperoxy-4-pregnene-3,20-dione 16fi-methyl-17a-hydroperoxy-5a-pregnane-3 fi-ol-l 1,20-

dione 16fi-methyl-17a-hydroperoxy-6a-fluoro-1,4-pregnadiene- 3,20-dione 16fl-methyl-17a-hydroperoxy-pregnane-3,1 1,20-trione IGfl-methyl-17a-hydroperoxy-5a-pregnane-3,11,20-trione 16fl-methyl-17u-hydroperoxy-pregnane-3 a-ol-ZO-one 3- acetate 1fi-methyl-17a-hydroper0xy-1,4-pregnadiene-115-01-330- dione, and 16fi-methyl-17a-hydroperoxy-9a,1 1fi-dichloro-4-pregnene- 3,20-dione.

The starting compounds listed above, upon treatment by the process of Example 2, yield the products set forth below:

EXAMPLE 3A 17a-methoxy-l6fi-methyl-17a-oxa-D-homo-5apregnane-3 [3-ol-20-one Repeat Example 2 but decrease the acetic anhydride from 3.5 ml. to 610 mgs. Isolate the resultant product in a manner similar to that described in Example 2. Fractions 23 to 32 afford the title product whose physical constants are as follows: M.P. 142-145 C. and [a] =3O (dioxane).

In a manner similar to that of this example, treat each of the starting materials enumerated in Example 2 and 3 isolate the respective resultant products in a manner similar to that described to obtain:

17ot-methoxy-16/3-methyl-17a-oxa-D-homo-pregnane-3,l1, r

-trione l7a-methoxy-1Gfi-methyl-17a-oxa-D-homo-5a-pregnane- 3,11,20-trione 17a-methoxy-16fi-methyl-17a-oxa-D-homo-pregnane-3ot- 01-2 0-one 17a-methoxy-16fl-methyl-17a-oxa-D-homo-1,4-pregnadiene-11fl-ol-3,20-dione, and 17a-methoxy-16j3-methyl-17a-oxa-D-homo-9a,1 lfi-dichloro-4-pregnene-3,ZO-dione, respectively.

EXAMPLE 3B 16-methyl-17a-oxa-D-homo-5a,16-pregnene- 3 fi-oI-ZO-one Continue to elute the column from Example 3A above with the ligroin-propylene glycol eluant used therein. Combine fractions 38 to 54 and obtain the title product having the same physical constants as the identical prodnot prepared in Example 2 above.

In similar manner, by utilizing the process of Example 3B on the starting material enumerated in Example 2, by removing the 17a-methoxy product from the column, and by continuing to elute the column the corresponding 16-methyl-17a-D-homo-16-pregnenes are obtained.

8 EXAMPLE 3c Continue to elute the column from Example 3B further and obtain from fractions 67 to 78 the title product of this example whose physical constants are as follows: M.P. 173-178 C. [a] =42.5, c.=dioxane, and a polymorph melting at 130-150 C.

Similarly, by the utilization of the process of this example on the starting material enumerated after Example 2 the following product may be obtained:

1 6;3-methyl-17a-oxa-D-homol7-iso-5-pre'gnene-3fl, 17pdiol-20-one l6,8-methyl-17a-oxa-D-homo-17-iso-4-pregnene-l7fl-ol-3,

20-dione 16/3-methyl-17-a-oxa-D-homo-17-iso-1,4-pregnadiene-l1a,

17,8-diol-3,20-dione 6a,16fl-dimethyl-17a-0xa-D-homo-17-iso-4-p1'egnene-175- 01-3 ,20-dione 16B-methy1-17a-oxa-D-homo-17-iso-5a-pregnane-3fi,17B-

diol-11,20-dione l6,8-methy1-17a-oxa-D-homo-6a-fluoro-17-iso-1,5-pregnadienel -01-3 ,20-dione 16,3-methyl-17a-oxa-D-homo-17-isopregnane-17/3-ol-3,1 1,

20-trione 16/i-methyl-17a-oxa-D-homo-17-iso-5a-pregnane-1713-01- 3,11,20-trione 16,8-methyl-l7a-oxa-D-homo-17-isopregnane-3p, 17fi-diol- 20'one 16/3-methyl-17a-oxa-D-homo-17-iso-1,4-pregnadiene-1lfl,

17fl-diol-3 ,ZO-dione and 16fi-methyl-17a-oxa-D-homo-9a, 1 15-dichloro-17-iso-4- pregnene-17/i-ol-3,20-dione, respectively.

EXAMPLE 4 16-methyl-17a-oxa-D-homo-5a,16-pregnene- 3 ,B-ol-ZO-one Suspend 3 gms. of 16B-methyl-17a-hydroperoxy-Sapregnane-3fl-ol-20-one in 80 ml. of dioxane and 8 ml. of 70% perchloric acid. Stir the mixture at room temperature for 18 hours and precipitate the product by the addition of 80 ml. of water. Dissolve the product in ml. of methanol and blanket the reaction mixture with nitrogen. Add an aqueous solution of 2 N sodium hydroxide to the reaction mixture with stirring until the solution is strongly basic (pH 12). Stir the reaction mixture for 2 hours at room temperature. Neutralize the reaction mixture with acetic acid and dilute the neutral solution with water to approximately 3 times its pre-dilution volume. Extract the mixture with ethyl acetate and wash the extracts with water. Dry the ethyl acetate solution over anhydrous sodium sulfate and concentrate the dried solution to a residue using the procedure of Example 1B and obtain from fractions 20 to 40, 1.02 gms. of 16-methyl- 17a oxa D-homo-5a,16-pregnene-3/i-ol-20-one whose physical constants are as follows: M.P. 159162 C. [oc] =79.5, A 278 mu (e=5,900).

EXAMPLE 5 16fl-methy1-17fi-methoxy-17a-oxa-D-homo-5 a,17- isopregnane-3 13-01 Dissolve 88 mg. of 16/3-methyl-17a-methoxy-17a-oxa- D-homo-5a-pregnane-3B-ol-20-one in 6 ml. of methanol containing 5-10 drops of acetic acid. Warm the mixture on a steam bath for 3 hours and add enough water (5- 20 ml.) to precipitate the product. Dry the precipitate at 60 C. and crystallize the dried product from a mixture of acetone-hexane to yield 45 mg. of the title product whose melting point and rotation are as follows: M.P. 180192 C. [a]

In a similar manner by treating other 16fl-methyl-17ualkoxy-l7a-oxa-D-homo-pregnanes with methanol and acetic acid in a manner substantially as described above, there is obtained the corresponding 17/3-alkoxy-17-isopregnane isomers thereof.

. Exemplary of the foregoing, the following 16,8-methyl- 17a-alkoxy-17a-oxa-D-homo-pregnanes may be employed in the process of this example:

Isolate the respective resultant products in a manner similar to that described in Example 5 to obtain respectively:

(1 16fi-methyl-17fi-ethoxy-17a-oxa-D-homo-5a,17-

isopregnane-3,20-dione (2) 16e-methyl-17/3-propoxy-17a-oxa-D-homo-4,17-

isopregnene-3,1 1,20-trione (3) 16fi-methyl-175-methoxy-17a-oxa-D-h0mo-1,4,l7-

isopregnadiene-l 1 fi-ol-S ,20-dione (4) 6a,16 9-dimethyl-17p-butoxy-17a-oxa-D-homo4,17-

isopregnene-3,20-dione (5 16B-methyl-17/8-isopropoxy-17a-oxa-D-homo-5,17-

isopregnene-3/8-ol-20-one (6) 16,8-methyl-17,8-methoxy-17a-oxa-D-homo-4,6,17-

isopregnadiene-3,20-dione (7 16,8-methyl-17 3-ethoxy-9a,1 lp-dichloro- 17 a-oxa-D- homo-4,17-isopregnene-3,20-dione (8) 16fi-methyl-17B-propoxy-6a,9a-difluoro-17a-oxa-D- homo-1,4,17-isopregnadiene-11fl-ol-3,20dione (9) 16B-methyl-17,6-methoxy-6a-chloro-17a-oxa-Dr homo-4,6,17-isopregnadiene-11B-ol-3,20-dione, and

( 6oz,16,B-dimethyl17fl-ethoxy-9ot-fluoro-17a-oxa-D- homo-1,4,17-isopregnadiene-11,B-ol-3,20-dione.

EXAMPLE 6 16-methyl-17a-oxa-D-homo-5u,16-pregnene-3t3-o1-20-one Suspend 5.2 gms. of 16fi-methyl-17a-hydroperoxy-5apregnane-3fi-ol-20-one in 150 ml. of acetic acid and add 20 ml. of isopropenyl acetate. Add 520 mg. of p-toluenesulfonic acid and stir the resulting mixture for 18-20 hours at room temperature. Dilute the reaction mixture with approximately 3 volumes (500 ml.) of water and extract with ethyl acetate. Concentrate the extracts to a residue in vacuo and dissolve the residue in methanol. Blanket the methanolic solution with argon and add 2 N potassium hydroxide to a pH of about 12. Stir the solution at room temperature for 1 hour while maintaining an argon atmosphere. Precipitate the product by adding Water to the methanolic solution, filter the suspension and dry the solid product. Chromatograph the dried product on 400 gms. of Chromosorb using the method described in Example 2 obtaining thereby 4.05 gms. of 16-methyl-17a-oxa-D-homo-5u,16-pregnene-3fl-ol-20-one.

Similarly, the foregoing procedure may be employed on other starting materials of which the following are exemplary:

16,8-methyl-17a-hydroperoxy-4-pregnene-3,20-dione 16fi-methyl-17a-hydroperoxy-1,4-pregnadiene-1 la-ol- 3,20-dione 6a,16fl-dimethyl-17a-hydroperoxy-4-pregnene-3,ZO-dione 16fl-methyl-17a-hydroperoxy-5a-pregnane-3fi-ol-1 1,20-

dione Y 16,8-methyl-17a-hydroperoxy-6a-fiuoro-1,S-pregnadiene- 3 fi-ol-ZO-one, and 16/3-methyl-17u-hydroperoxy-pregnane-3,1 1,20-trione.

By employing the procedure of Example 5 on the compounds just enumerated the following products may be obtained:

16-methyl-17a-oxa-D-homo-4,16-pregnadiene-3,20-dione 16-methyl-17a-oxa-D-homo-1,4,16-pregnatriene-11a-o1- 3,20-dione 6oz, l6-dimethyl-17a-oxa-D-homo-4,16-pregnadiene-3-20- dione 16-methyl-17a-oxa-D-homo-5u,16-pregnene-3fl-ol-11,20-

dione 16-methyl-17a-oxa-D-homo-6a-fiuoro-1,5,16-pregnatriene- 3 ,B-ol-ZO-one, and

16-methyl-17a-oxa-D-homo-16-pregnene-3,1 1,20-trione.

EXAMPLE 7 16-methyl-17a-oxa-D-homo-5a,16-pregnene-3fl-ol-20-one Dissolve 100 mgs. of 16,8-methyl-17a-oxa-D-homo-17- isopregnane-BB,17fi-diol-20-one in 20 ml. of methanol. Add a few (5-15) drops of 2 N hydrochloric acid to the solution and maintain at about 25 C. for 48 hours. Precipitate the product by the addition of water and chromatograph the dried precipitate on Chromosorb (250 grams) using ligroin saturated with propylene glycol as the eluent and monitor the efiluent by chromatographing on paper a portion (0.1 ml.) of each (10 ml.) fraction. Combine the fractions of similar mobility as determined by spraying the dried paper with a methanol phosphomolybdic acid spray and measuring the R of the spots that appear on heating. Isolate the product as described in Example 2 to obtain the title compound which after crystallization from acetone-hexane melts 159-162 C. has an [a] =79.5 and a A at 278 m (6 5,900).

EXAMPLE 8 6a,16-dimethyl-17a-oxa-D-homo-5a,16-pregnane- 3B-ol-20-one Dissolve 630 mgs. of 6a,16 3-dimethyl-17a-oxa-D- homo-5a-pregnane-3fi,17u-diol-20-one 17-methyl ether in ml. of tetrahydrofuran and about 1.0 ml. of 2 N hydrochloric acid and warm the solution on the steam bath for about one hour. Precipitate the product by the addition of water to the reaction mixture and crystallize the precipitate from acetone-hexane to obtain the title product.

EXAMPLE 9 16-methyl-17a-oxa-D-homo-5a-pregnane-35,16,17-triol- 20-one Dissolve 717 mg. of 16-methyl-17a-oxa-D-homo-5a,16- pregnene3,3-ol-20-one in 30 ml. of ethyl ether and 1 ml. of pyridine. Prepare a solution of 500 mg. of osmium tetroxide in 15 ml. of ethyl ether. Mix the two solutions and store the mixture in the dark at room temperature for 3 days. Collect the precipitated product by filtration and wash with ethyl ether. Dissolve the product in 125 ml. of ethanol and add ml. of a 2% sodium metabisulphite solution. Reflux the mixture for about 1 /2 hours, filter the suspension and remove the greater part of the ethanol by distillation. Cool the mixture and extract the product with ethyl acetate. Concentrate the ethyl acetate extracts to a residue and crystallize from aqueous ethanol 1 1 to yield the title product with the following physical constants: M.P. 166177 C. [a] =87 I claim: 1. A compound selected from the group consisting of steroids having the formulae:

wherein R is a member selected from the group consisting of hydrogen and methyl; R is a member selected from the group consisting of hydrogen and lower alkyl when R is p-oriented, and lower alkyl when 0R is aoriented; W is a member selected from the group consisting of oxygen, (H, ocOV) and (H, 180V), V being a member selected from the group consisting of hydrogen and lower alkanoyl; X is a member selected from the group consisting of hydrogen and halogen having an atomic weight less than 126; Y is a member selected from the group consisting of oxygen, (H, ,BOH), (H, BOH), hydrogen provided X is hydrogen, and (H, fiCl) provided X is chlorine; Z is a member selected from the group consisting of hydrogen, methyl, fluorine and chlorine; and the l-dehydro, 4-dehydro, S-dehydro, 1-4-bis-dehydro and the 1,5-bis-dehydro analogs thereof.

2. 16/8 methyl 17a oxa D homo 5a pregnanc- 170; ol 3,20 dione l7-methyl ether.

3. 16B methyl 17a oxa D homo 5a,17 isopregnane 17 3 ol-3,20-dione 17-methyl ether.

4. 16B methyl 17a oxa D homo 5a,l7-lSO pregnane-3fi,l7fl-diol-20-one 3-acetate.

5. 16 methyl -17a oxa D homo-4,16-pregnadiene- 3,20-dione.

6. 16B methyl 17a oxa D homo-4,17-is0-pregnene-l7 3-ol-3,20-dione 17-methyl ether.

7. 16 8 methyl 17a oxa D homo-5pregnene-3fl, l7ot-diol-20-one 17-methyl ether.

8. A process for preparing the 16-dehydro and 17- hydroxy compounds of claim 1 which comprises treating a 3 oxygenated 16,6 methyl 17oz hydroperoxy pregnane-ZO-one in a tertiary amine with a member selected from the group consisting of a lower alkanoyl anhydride, a lower alkanoyl chloride, and a lower alkanoyl bromide.

9. A process according to claim 8 wherein said tertiary amine is pyridine and said lower alkanoyl anhydride is acetic anhydride.

10. A process for preparing the compounds of claim 1 which comprises treating a 3 oxygenated -16/3 methyl- 17a hydroperoxy pregnane 20-one in a tertiary amine with a member selected from the group consisting of a lower alkanoyl anhydride, a lower alkanoyl chloride, and a lower alkanoyl bromide; followed by treating the thereby formed l6-dehydro and the l7-hydroxy compounds of claim 1 with an alkali in aqueous lower alkanol in an inert atmosphere.

11. A process for preparing the l6-dehydro and the l7-hydroxy compounds of claim 1 which comprises subjecting a 3-oxygenated 16p methyl 17a hydroperoxy-pregnane-ZO-one to the action of a strongly acidic medium.

12. A process for preparing the compounds of claim 1 which comprises subjecting a 3-oxygenated-l6fl-methyl- 17a hydroperoxy pregnane-ZO-one to the action of a strong acid, followed by treatment of the thereby formed l6-dehydro and the 17-hydroxy compounds of claim 1 with an alkali in aqueous lower alkanol in an inert atmosphere.

13. A process according to claim 12 wherein the strongly acidic medium comprises a mineral acid in a water miscible, non-hydroxylic, organic solvent.

14. A process according to claim 13 wherein said mineral acid is perchloric acid and said water miscible nonhydroxylic, organic solvent is a member selected from the group dioxane and tetrahydrofuran.

15. A process according to claim 12 wherein the strongly acidic medium comprises acetic acid, isopropenyl acetate and a hydrocarbon sulfonic acid.

References Cited UNITED STATES PATENTS 2,806,039 9/1957 Murray et a1 260345.2 3,064,011 11/1962 Knox 260345.2 3,362,964 1/1968 Baran 260--345.2 XR 3,378,570 4/ 1968 Baran 260-3452 HENRY R. JlLES, Primary Examiner US. Cl. X.R.

fgggy UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent no, 5, 57,677 Dated September l6, 1969 Inventor-( n N. Gardner It is certified that: error appears in the above-ident1fied patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 6 "oxa-fia-D-lwmo" should. read ---oxa-5Q1-D- nomo--. Column 3, line 'r, "implicity" snoulc; read --implicitly--. Column "f, line 21 and 22, 4,16 -prcgna l'Yozflnethoxy-l6 {5-mcti1yl lTozoxaDnomo-50: should read +,lo pregnadiene -'j,2U-diono respectively-. Column 0,

line C, "c.=c'iioxar1e" should read ---C=l dioxane. Column 5, line ll, "material should read ---materials--. Column 6, line l2, "product should read --products-. Column ll, line 2, "166 -l'{"{ C.[Oj 7 07 SiiOuld read ---l66 -l7'f 17 D SIGNED AN'D SEALED mew (SEAL) Attest:

EdwardMFIetchegIr.

JR- Attes WILLIAM E. SW,

tmg Officer Commissioner of Pat-ants 

